Certain 4-(chlorophenylhydrazono)-2-isoxazolin-5-ones



United States Patent 3,370,064 CERTAIN 4-(CHLOROPHENYLHYDRAZONO)-2- ISOXAZOLIN-S-ONES Michael Joseph Augustine Geoghegan, John Angus WiL liam Turner, and Peter Frank Hilary Freeman, Bracknell, England, and Lindsay Anderson Summers, Newcastle, New South Wales, Australia, assignors to Imperial Chemical Industries Limited, London, England, a corporation of Great Britain No Drawing. Continuation-impart of application Ser. No. 147,741, Oct. 26, 1961. This application Feb. 16, 1965, Ser. No. 433,162 Claims priority, application Great Britain, Nov. 2, 1960, 37,645/60; July 31, 1961, 27,676/61 7 Claims. (Cl. 260-307) This application is a continuation-in-part of Ser. No. 147,741 filed Oct 26, 1961, and now abandoned.

This invention relates to the use as fungicides of Z-isoxazolin--ones, to new 2-isoxazolin-5-ones and to processes for their preparation.

The invention includes fungicidal compositions comprising as active ingredient a 2-isoxaZolin-5-one of the formula:

where R is a carboxymethyl or carboxyethyl radical, or an alkyl radical of 1-6 carbon atoms (especially 1-4 carbon atoms), such as methyl, ethyl, propyl and butyl, optionally having a substituent hydroxy or cyano group or a halogen atom and R is a substituted or unsubstituted phenyl or naphthyl radical, and a carrier for the active ingredient, said carrier comprising a solid inertdiluent, or a liquid diluent containing a surface active agent.

Where the group R is a substituted phenyl or naphthyl radical the substituents can be, for example, one or more of the following: alkyl and alkoxy radicals of from 1 to 12 and especially from 1 to 4 carbon atoms, cycloalkyl, aryl (or substituted aryl), arylazo (or substituted arylazo), aryloxy, halogen, carboxy, alkoxycarbonyl, carboamino, cyano, nitro, hydroxyl, trifluoromethyl, amino, N-alkylamino, N,N-dialkylamino, sulphonic acid, sulphonamido, aminosulphonyl or thiocyanate radicals.

It has been found that compounds where the group R is a chloro-substituted phenyl radical or a lower alkylsubstituted phenyl radical possess useful fungicidal properties as is shown in the examples. Examples of di-substituted phenyl radicals are those in which the substituents are two alkyl or two alkoxy radicals, two atoms of any of the halogens, alkyl and alkoxy, alkyl and nitro, alkoxy and nitro, alkyl and halogen or alkoxy and halogen.

The compound used as active ingredient can if desired be in the form of one of its salts, for example its sodium or potassium salt.

Some of the compounds of the invention have been found to be very effective when applied as foliage fungicides, some when applied as seed-dressings and some as soil fungicides; and the exact form of the fungicidal composition depends to a large extent upon the use to which the composition is to be put and the pathogen which it is wished to control. For example, the compositions can be powders,- solutions, dispersions or pastes; Where they are powders they can be ones in which the active ingredient is in admixture with a powder diluent. Where the composition is liquid it can be one in which the active ingredient is dissolved or suspended in a suitable liquid, for example water or a suitably non-phytotoxic liquid. The ingredients used with the active ingredient in any of the fungicidal compositions of this invention can be substances known to the art as being suitable in the formulation of fungicidal compositions, for example surface active substances such as wetting anddispersing agents, binders, stickers, corrosion. inhibitors and stabilising agents.

Fungicidal compositions of the invention which have been found to be useful as liquid seeddressings are solutions of the sodium salt of 3-methyl-4-phenylhydrazono 2-isoxazolin-5-one in B-ethoxyethanol, diacetonyl alcohol or ethylene glycol, and in particular solutions in which the sodium salt is present in a proportion of about 25% w./v.

The invention also consists in the new 2-isoxazolin-5- ones of the general formula:

where R is an alkyl radical of 2-6 (especially 2-4) carbon atoms, a carboxyalkyl'or alkoxycarbonylalkyl-radical of not more than 4 carbon atoms, and R is a substitute'd or unsubstituted phenyl or naphthyl radical; or where R is an alkyl radical of l6 (especially l-4') carbon atoms or a carboxyalkyl or alkoxycarbonylalkyl radical of not more than 4 carbon atoms and R is a chlorosubstituted' phenyl radical; and their salts. 1

The 2-isoxazolin-5-ones useful as active ingredients in the fungicidal compositions of this invention can be obtained, for example, by a process in which there is reacted together a keto-ester of the formula:

where R is an alkyl radical of 1-6 (especially 14) carbon atoms or a carboxyalkyl or an alkoxycarbonylalkyl radical of not more than 4 carbon atoms and R is an alkyl radical of 1-4 carbon atoms, the appropriate substituted or unsubstituted phenyl or naphthyl diazonium salt and hydroxylamine or a salt of hydroxylamine. The process is conveniently performed with the reactants dissolved or dispersed in water or in a mixture of water and ethanol. The diazonium salt can be conveniently produced in situ by the reaction of the appropriate amine and nitrous acid as is illustrated in the examples of this specification.

A second process for the preparation of the 2-isoxazolin- 5-ones is one in which an azo compound of the formula:

where R and R have the meanings given to them in connection with the first process described above and R is a substituted or unsubstituted phenyl or naphthyl radical, is reacted with hydroxylamine or a salt thereof. This process is conveniently carried out in mildly alkaline conditions, for example with the reactants dissolved or dispersed in water or in a mixture of water and ethanol and in the presence of caustic alkali or sodium acetate, or in pyridine. Since reaction at room temperature is generally slow the process is preferably carried out at an elevated temperature, for example at a temperature in the range 60--1l5' C. The azo compound used in this second process can conveniently be obtained in situ by the reaction of a keto-ester of formula:

and the appropriate diazonium salt.

In the preparation of compounds of this invention where the group R is a methyl group satisfactory results have been obtained using diketene instead of the keto-ester.

The invention also consists in a method of combating plant pathogens, in which the foliage of a plant susceptible to such pathogens, seed from which the plant can be grown or soil in which the plant is to be grown, is treated with a compound or fungicidal composition as hereindescribed.

The invention is illustrated by the following examples:

Example 1 perature being allowed during this time to rise slowly to about 20 C., and filtered. The solid residue which was obtained on the filter was washed with water and crystallised from a mixture of ethanol and benzene. The product thus obtained was 3 methyl 4 (3-methylphenylhydrazono)-2-is0xazolin-5-0we, as yellow crystals, M.P. 172 C.

Example 2 3-chloro-4-methylaniline (7.1 g.) was suspended in water (60 ml.) and the mixture acidified with concentrated aqueous hydrochloric acid (18 ml.). After cooling to C. the mixture was diazotised with a solution of sodium nitrite (4.0 g.) in water ml.). The solution so obtained was then added slowly with stirring to a cold (5 C.) mixture of ethyl acetoacetate (6.6 g.) in ethanol (170 ml.) and water ml.) to which had been added anhydrous sodium acetate (24 g.). The mixture was allowed to stand at about 20 C. for 15 hours, filtered and the solid residue obtained on the filter washed with water. The residue was dissolved in boiling ethanol ml.)

and to this solution there was added slowly a hot solution of hydroxylarnine hydrochloride (3.5 g.) in water 100 ml.) to which had been added anhydrous sodium acetate (8.2 g.). The mixture so obtained was heated under reflux for 15 minutes, allowed to stand for 15 hours at about 20 C. and filtered. The solid residue which was obtained on the filter was washed with water and crystallised from ethanol. The product thus obtained was 3-m-ethyl-4-(3- chloro 4 methylphenylhydrazono-Z-is0xaz0lin-5-0ne as yellow crystals, M.P. 192 C.

Examples 3-33 A number of other 2-isoxazolin-5-ones have been prepared by the general methods described above in Examples 1 and 2, but using the appropriate amine in each instance instead of rn-toluidine and 3-chloro-4-methylaniline used respectively in those examples. These other Z-isoxazolin-S-ones are set out in the table below as Examples 3-33. The products of Examples 3-15 were obtained by the process of Example 1 while those of Examples 16-33 were obtained by the process of Example 2. The products of Examples 3-33 are believed to all have the general formula:

where R is a substituted benzene ring and the products are identified in each example by the meaning given to R in the column having that heading. For the sake of convenience the double bonds have been omitted from all the benzene rings shown. The melting point shown against each product is that obtained using a sample of the product which had been purified by recrystallisation.

TABLE I Example Product R1 M.P. 0.) Appearance OMe I l 3 l 193 Yellow crystals.

4 OMe 208 Orange crystals.

I 5 C 150 Do.

6 Q01 192 Yellow crystals.

l 7 C 168 Orange crystals.

Ma I 8 Q 142 EtO 10 OEt Do.

02 11 214 Yellow crystals.

TABLE I-Continued Exlefmple Product R1 M.P. 0.) Appearance Me H I 12 -C -Me 199 Do.

Me Me I 13 -C 136 Orange crystals.

N02 H H I 14 C 205 Brown crystals.

| 15 QMe 128 Orange crystals.

I 16 -c1 148'. Do.

I 17 171 Do.

I 18 -C c1 193 Yellow crystals.

I 19 -C 163' Brown crystals.

r Me 01 I I 20 C 194 Yellow crystals.

I 21 148 Do:

I 24 168 Do.

I s G 5 Do.

26 @F 165 Orange crystals.

I 27 C 200 Yellow crystals.

TABLE I Continued Example Product R; M.P. 0.) Appearance l 28 -01 160 Do.

I 29 r 182 Bed crystals.

i 30 108 Orange crystals.

(I) O 0 El; 31 C 96 Yellow crystals.

EtO 0 (ll 32 O 120 Do.

as C N=N 20s Briek red crystals.

Example 34 Ethylacetoacetate (6.6 g.), hydroxylarnine hydrochloride (3.5 g.), m-chloroaniline (6.4 g.) and concentrated aqueous hydrochloric acid (10 ml.) were added to ethanol (10 ml.) and the mixture cooled to about C. A cold aqueous solution of sodium nitrite (4.0 g.) in Water ml.) was added slowly to the mixture with stirring so that the temperature did not exceed 10 C. The mixture was then stirred for a further 6 hours, the temperature being allowed during this time to rise slowly to about C., and filtered. The solid residue which was obtained on the filter was washed with water and crystallised from a mixture of ethanol and benzene. The product thus obtained was 3 methyl-4-(3'-chlorophenylhy'drazono) -2- isoxazolin-S-one as brown crystals, M.P. 162 C.

Example 35 p-Ethylaniline (6.1 g.) was suspended in water (60 ml.) and the mixture acidified with concentrated aqueous hydrochloric acid (18 ml.). After cooling to 5 C. the mixture was diazotised with a solution of sodium nitrite (4.0 g.) in water (15 ml.). The resulting solution was added slowly with stirring to a cold (5 C.) mixture of ethyl acetoacetate (6.6 g.) in ethanol (170 ml.) and water ml.) to which had been added anhydrous sodium acetate (24 g.). The mixture was allowed to stand at about 20 C. for 15 hours and the heavy oil which was obtained was separated from the aqueous layer and washed with water. The washed oil was dissolved in boiling ethanol (100 ml.) and to this solution there was added slowly a hot solution of hydroxylamine hydrochloride (3.5 g.) in water (100 ml.) to which had been added anhydrous sodium acetate (8.2 g.). The mixture so obtained was heated under refiux for 15 minutes, allowed to stand for 15 hours at about 20 C. and filtered. The solid residue which was obtained on the filter was washed with water and crystallised from ethanol. The product thus obtained was 3- methyl-4-(4-eflzylphenylhydrazono) 2 -is0xaz0lin-5-o1ze as yellow crystals, M.P. 154 C.

Example 36 The process described in Example 35 was repeated except that the p-ethylaniline (6.1 g.) was replaced. by o-ethylaniline (6.1 g.). The product when crystallised from ethanol was 3-methyl-4-(2'-ethylphenylhydraz0m0)- Z-isoxazolin-S-one as orange crystals, M.P. 122 C.

Examples 37, 38 and 39 describe the preparation of various salts of 2-isoxazolin-5-ones.

Example 37 3 methyl-4-(3-methylphenylhydrazono)-2-isoxazolin- 5-one (3 g. of the compound obtained as the product .of Example 1 above) was suspended in 10% aqueous sodium hydroxide solution (30 ml.) and ethanol (30 ml.) was added. The mixture was heated at about C. for 2 minutes and the resultant solution was filtered. On cooling the resulting filtrate, a crystalline solid precipitated which was removed by filtration and was washed with ether. The product thus obtainedwas the sesquihydrate 0f the sodium salt of 3-methyl-4-(3'-methylphenylhydraz0n0)-2-isoxaz0lin-5-one as yellow needles which slowly decomposed on heating but were not completely fused at 300 C.

Example 38 The process described in Example 37 was repeated except that the 3-methyl-4-(3-methylphenylhydrazono)-2 isoxazolin-S-one (3 g.) was replaced by 3-methyl-4-(4'- chlorophenylhydrazono)-2-isoxazolin-5-one (3 g. of the compound obtained as product of Example 6 above). The product was the trihydrate of the sodium salt of 3-methyl- 4-(4'-chlor0phenylhydraz0no)-2-is0xazolin-5-one as yellow crystals, M.P. C. with decomposition.

Example 39 The process described in Example 37 was repeated except that the 3-methyl-4-(3'-methylphenylhydrazono)-2- isoxazolin-S-one (3 g.) was replaced by 3-methyl-4-.(4- chlorophenylhydrazono)-2-isoXaZolin-5-one (3 g. of the compound obtained as product .of Example 6 above) and the 10%aqueous sodium hydroxide (30 ml.) by 10% aqueous potassium hydroxide-(30 ml.). The product was the sesquihydrate of the potassium salt of 3-methyl-4- (4-chl0r0phenylhydraz0n0)-2-is0xazolin-5-0ne as yellow crystals which decomposed at 170-180 C.

Example 40 This example describes the preparation of 3-methy1- 4-(2z4':5'-trichlorophenylhydrazono) 2 isoxazolin-S- one by a process which is a modification of the general process described in example 2 above. The modification consists essentially of the use of pyridine, in place of ethanol, in the processs third stage where the product of The wet, crude intermediate (23 g.) obtained by reacting ethyl aceto-acetate (6.5 g.) with 2:4:5-trichlor0- phenyl-diazonium chloride by the general method of Example 2 was mixed with hydroxylamine hydrochloride (3.5 g.) and pyridine (75 ml.) and the mixture was refluxed for 1 hour. The product obtained was then poured into iced water containing hydrochloric acid and the solid which precipitated was removed by filtration and recrystallised from ethanol yielding 3-methyl-4-(2':4:5-trichlorophenylhydrazono)-2-isoxazolin -5-one as a reddishbrown solid, M.P. 151 C.

Exam les 41-78 A number of other 2-isoxazolin-5-ones have been prepared by the general method described in Examples 1, 2 or 40 above, but using various keto-esters and the appropriate amine in each instance. These 2-is0xazolin-5-ones are set out in Table II below as Examples 41-78.

The products of Examples 41-78 were obtained by processes involving a keto-ester of the formula:

and a diazonium chloride of formula: CIN=NR 10 and are believed to all have a structure corresponding to the general formula:

where R is an alkyl or alkoxycarbonylalkyl radical and R is a substituted benzene ring.

In Table II the product of each example is identified by reference to the nature of the groups R and R and for the sake of convenience the double bonds have been omitted from all the benzene rings depicted.

With the exceptions of Examples 52, 67,68, 72, 73, 75 and 76, the compounds of all the examples in Table II were obtained using the general process describing in Example 2 above, but using the appropriate keto-ester and amine in each instance. With regard to the exceptions, the compounds .of Examples 67 and 68 were obtained by the general process of Example 1 above; and the compounds of Examples 52, 72, 73, 75 and 76 by the general process .of Example 40, using the appropriate keto-ester and amine in each instance.

TABLE II Example Product R R1 M.P.(C.)

41 CH8 Q 48 nCiHn 42 CH3 Grimm 92 4a CH; Q-noHHM 91 44 0 45 CH3 Q 162 4s 0H3 Ooooonn 204 47 CH3 00H 227 48 CH3 N(CH3)2 17b 49 CH3 @sonvm 22s 50 CH3 @Br 194 52 CH3 soN V 174 CQHE 53 on, C

TABLE II-Continued Example Product R R1 M.P. 0.)

7o 02115 OCZH 145 71 Gene 0 160 01 C1 72 Gene G 150 74 C2H5OOCCH2 O 126 75 olHPooo-om Q 115 76 C2H5OOC-CH2 113 3 77 C2H5OOC-CH2 oon 127 7a C7H5OOC--CH: Q 220 Examples 7 TABLE IIIC0ntinued Table III below includes as Examples 79-88 a number of further 2-isoxazolin-5-ones which have been formu- Exam 16 No Product p R R M P C 0) lated as fungicidal compositions. The vanous compounds 1 are identified in Table 111, as in Tables 1 and 11, by refer- CH ence to the nature of the groups R and R The double 1 a the bonds have, for convenlence, been omitted from all 85 H CH3 C1 148 structures depicted.

TABLE III I P d t 86 CH 203 ro uc I Example R R; M.P. 0.

79 CH3 0 190 87 CH 1 8 so. CH: @0113 204 9 88 0H3 0N0; 176 81 CH3 160 1 With decomposition. CHaO I 82 CH3 0 178 Good results have been obtained usmgv funglcldal compositions of this invention as seed dressings, and in Table H000 IV below there is shown compounds which have been I found to be active against a number of economically im 3 CH3 0 1 P ant f ngus and bacterial diseases. Similarly, Table V K shows compounds found to be active against various foli- CH3 age fungus diseases. The active ingredients of the com- I positions tested have been referred to below, for simplicity, s4 0H @0113 12s by the number of the examples in Tables I, II or III in which they appear.

TABLE IV.SEED DRESSINGS Active Ingredientthe Disease Crop Product of Example Nos.

Pythium ultimum Peas 5, 11, 16, 17, 79 and 81. Fusarium culmoru'm ..do- 6, 7, 10, 26 and 81.

22. Tilletia caries Wheat- 6, 82 and 84.

TABLE V.-FOLIAGE FUNGICIDES Active Ingredient-the The compounds of Examples 5, 6, 11, 16, 26, 81, 82 and 84 have been found to be active against the soil-borne disease Rhizoctonia solani.

The fungicidal 4-arylhydrazono compounds of the present application were first described as 4-arylazo compounds in Ser. No. 147,741. This is due to the fact that the compounds in question can exist in different tautomeric forms. However, in the solid state in which the products described herein are made, these products are more correctly identified with the arylhydrazono structure rather than the tautomeric arylazo structure attributed tothese same compounds in Ser. No. 147,741. It is intended that the claims herein should cover not only the use of the 4- arylhydrazono compounds but the tautomers thereof as well.

What we claim is:

1. A Z-isoxazolin-S-one which in one tautomeric form has the general formula:

H R-C-C=N N-R1 where R is selected from the group consisting of alkyl of 2-6 carbon atoms, carboxyalkyl and alkoxycarbonylalkyl radicals of up to 4 carbon atoms, and R is chlorophenyl.

2. A 2-isoxaZ0lin-5-one of the formula shown in claim 1 wherein R is alkyl containing from 1 to 4 carbon atoms and R is chlorophenyl.

3. 3 methyl 4-(2'-chlorophenylhydrazono)-2-isoxazolin-S-one.

4. 3 methyl 4 (3-chlorophenylhydrazono)-2-isoxazolin-5-one.

5. 3 methyl 4 (4'-chlorophenylhydrazono)-2-isoxazolin-S-one.

6. An alkali metal salt of a 2-isoxazolin-5-one as defined in claim 1.

7. A 2-isoxazolin-5-one which in one tautomeric free base form has the general formula:

where R is selected from the group consisting of alkyl of 1-4 carbon atoms and carboxyalkyl and alkoxycarbonylalkyl wherein the alkyl contains 1-4 carbon atoms, and R is chlorophenyl.

References Cited UNITED STATES PATENTS 2,999,047 9/1961 Model et al 167--33 3,090,721 5/1963 Uhlenbroek et a1. 167-33 3,194,810 7/1965 Formaini et a1 260-307 3,202,673 8/ 1965 Metivier et al. 260-307 OTHER REFERENCES Bulow et al., Berichte, Volume 44, (1911), pp. 238-50.

Burger, Medicinal Chemistry, Interscience, 1960, page 75.

Meyer, Compt. Rend., Volume 154 (1912), pp; 1511- 14.

Schiff et al., Berichte, Volume 30 (1897), pp. 1159-66.

ALEX MAZEL, Primary Examiner.

HENRY R. JILES, Examiner.

RICHARD J, GALLAGHER, Assistant Examiner. 

7. A 2-ISOXAZOLIN-5-ONE WHICH IN ONE TAUTOMERIC FREE BASE FORM HAS THE GENERAL FORMULA: 